A sex-specific microRNA-96/5HT1B Axis influences development of pulmonary hypertension

Wallace, E. , Morrell, N. W., Yang, X. D., Long, L., Stevens, H., Nilsen, M., Loughlin, L., Mair, K. M., Baker, A. H. and MacLean, M. R. (2015) A sex-specific microRNA-96/5HT1B Axis influences development of pulmonary hypertension. American Journal of Respiratory and Critical Care Medicine, 191(12), pp. 1432-1442. (doi:10.1164/rccm.201412-2148OC) (PMID:25871906) (PMCID:PMC4476563)

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Abstract

Rationale: Females are predisposed to pulmonary arterial hypertension (PAH); evidence suggests that serotonin, mutations in the bone morphogenetic protein receptor (BMPR) II gene, and estrogens influence development of PAH. The 5-hydroxytryptamine 1B receptor (5-HT1BR) mediates human pulmonary artery smooth muscle cell (hPASMC) proliferation. Objectives: We aimed to determine whether selected microRNAs (miRNAs) expressed in PASMCs are influenced by sex, BMPR-II mutations, and estrogens, and contribute to PASMC proliferation in PAH. Methods: Expression levels of miRNAs targeting genes related to PAH, estrogen, and serotonin were determined by quantitative RT-PCR in hPASMCs and mouse PASMCs harboring a heterozygous mutation in BMPR-II (BMPR-IIR899X+/− PASMCs). miRNA-96 targets 5-HT1BR and was selected for further investigation. miRNA target validation was confirmed by luciferase reporter assay. Precursor miRNA-96 was transfected into hPASMCs to examine effects on proliferation and 5-HT1BR expression. The effect of a miRNA-96 mimic on the development of hypoxic pulmonary hypertension in mice was also assessed. Measurements and Main Results: miRNA-96 expression was reduced in BMPR-IIR899X+/− PASMCs from female mice and hPASMCs from female patients with PAH; this was associated with increased 5-HT1BR expression and serotonin-mediated proliferation. 5-HT1BR was validated as a target for miRNA-96. Transfection of precursor miRNA-96 into hPASMCs reduced 5-HT1BR expression and inhibited serotonin-induced proliferation. Restoration of miRNA-96 expression in pulmonary arteries in vivo via administration of an miRNA-96 mimic reduced the development of hypoxia-induced pulmonary hypertension in the mouse. Conclusions: Increased 5-HT1BR expression may be a consequence of decreased miRNA-96 expression in female patient PASMCs, and this may contribute to the development of PAH.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacLean, Professor Margaret and Baker, Professor Andrew and Wallace, Miss Emma and Loughlin, Mrs Lynn and Stevens, Dr Hannah and Nilsen, Mrs Margaret and Mair, Dr Kirsty
Authors: Wallace, E., Morrell, N. W., Yang, X. D., Long, L., Stevens, H., Nilsen, M., Loughlin, L., Mair, K. M., Baker, A. H., and MacLean, M. R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:American Journal of Respiratory and Critical Care Medicine
Publisher:American Thoracic Society
ISSN:1073-449X
ISSN (Online):1535-4970
Copyright Holders:Copyright © 2015 American Thoracic Society
First Published:First published in American Journal of Respiratory and Critical Care Medicine 191(12):1432-1442
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher.

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
573731Gender and the development of pulmonary arterial hypertension: regulation of genes from mouse to manMargaret MacLeanBritish Heart Foundation (BHF)RG/11/7/28916RI CARDIOVASCULAR & MEDICAL SCIENCES
573733Gender and the development of pulmonary arterial hypertension: regulation of genes from mouse to manMargaret MacLeanBritish Heart Foundation (BHF)RG/11/7/28916RI CARDIOVASCULAR & MEDICAL SCIENCES